The objective of this research program is to define the molecular mechanisms that regulate the inflammatory process. One effector molecule that has been implicated as a regulator of inflammatory responses is transforming growth factor beta (TGF-beta). The TGF-beta1(-/-) mouse provides a model to explore the in vivo regulatory role of TGF-beta1. These mice develop multifocal inflammatory lesions in vital organs and die within 3-4 weeks. TGF-beta1 (-/-) mice initially exhibit increased poly- and autoreactive antibodies of the IgM isotype. As animals become increasingly symptomatic, this initial wave of IgM antibodies is replaced by those of an IgG isotype, a pattern consistent with autoantigen-driven immune responses. Plasma IL-6 and IFN-gamma levels and mRNA expression (by semi-quantitative RT-PCR) for IFN-gamma, IL-4, IL-6 and IL-10 are elevated in TGF-beta1 (-/-) lymphoid and target organs, suggesting potential mechanisms whereby lack of TGF-beta1 could lead to B cell activation and polyclonal expansion in TGF-beta1 (-/-) mice. The production of antibodies leads to autoimmune-like lesions in several tissues. Inflammatory sites within the salivary gland, characterized by periductal lymphocytic infiltration and increased proliferation, cytokine mRNA expression, and IgG-positive cells resemble lesions of Sj[unreadable]gren's syndrome. Glandular atrophy and loss of acini with reduced saliva production appear to contribute to the wasting syndrome characteristic of the TGF-beta1(-/-) mice. In an attempt to block inflammation and rescue the mice, TGF-beta1(-/-) mice were treated with synthetic fibronectin (FN) peptides. Daily systemic injection of FN peptides not only prevented tissue infiltration and weight loss in TGF-beta1(-/-) mice, but also reversed the acinar and ductal derangements, suggesting that the inflammation compromises glandular structure and function. These TGF- beta1(-/-) mice provide an important model of autoimmune disease which can be utilized in the design of therapeutic interventions.